The Collaborative Study on the Genetics of Alcoholism (COGA) is a tightly integrated and interdisciplinary project that involves participation of investigators from multiple sites spanning a broad range of expertise. The goals of COGA are to identify and characterize genes in which variations confer risk for, or protection from, the development of Alcohol Use Disorders (AUDs) and related phenotypes; to understand the mechanisms by which these variants work at the molecular and cellular level; and to understand how genetic, environmental, and neurocognitive factors interact to influence the developmental trajectories of alcohol use and AUDs through an ongoing prospective study of at-risk individuals. COGA has assembled a unique sample of large, ethnically diverse families densely affected by AUDs and a set of comparison families, with rich phenotypic assessments in multiple domains: clinical, behavioral, neurophysiological, neuropsychological and environmental. The overall specific aims are to: Aim 1. Advance understanding of complex phenotypes related to AUDs; Aim 2. Identify additional genes contributing to risk for AUD, related phenotypes, including endophenotypes; Aim 3. Explore potential mechanisms of action of key genes; Aim 4. Examine effects of genes and environmental influences on clinical and neurophysiological phenotypes related to the vulnerability for risky drinking, AUDs and SUDs across development. In responding to the RFA, the study has three inter-dependent projects and three essential cores. The three projects are each focused on different aspects of these core aims: Genetic and Functional Studies of Alcohol Use Disorders and Related Phenotypes - Using a range of alcohol-related phenotypes, identifies variants across allelic spectrum and studies their mechanisms of action; Prospective Study of Genetic and Environmental Influences on Alcohol Use and Disorders Across Development - Longitudinally studies genetic and environmental influences and their interaction on development of AUDs during adolescence and emerging adulthood; Neurophysiological Phenotypes, Brain Maturation and Development of Alcohol Use and Related Disorders - Identifies genes related to novel neurocognitive phenotypes and their effects on trajectories of neurocognitive development and AUDs. The cores (Administrative Core, Data Management Core, and NIAAA/COGA Sharing Repository Core (NCSR)) provide critical support to each project, ensuring that key cross-study and cross site functions are centralized. Through tight coordination of this interdisciplinary study, we will go from identifyin genes, in which variants affect risk for AUDs and related phenotypes to understanding how they act at multiple levels, from molecular and cellular, to behavioral, neurophysiological, cognitive phenotypic, as a function of development. The delineation of the pathways and genes contributing to alcohol use and AUDs will impact treatment and prevention of AUDs in those at greatest risk.